Fumaric acid

Fumaric acid: production and separation

Fumaric acid is a valuable compound used in foods, beverages, detergents, animal feed, pharmaceuticals and miscellaneous industrial products. It is produced on a large scale by the petrochemical route but the current tendency is towards implementing "green production" and environmental friendly technologies like biotechnological production of fumaric acid using low-cost raw materials. In this context, numerous studies focus on improving the fermentation process not only by using renewable raw material and genetically modified microorganisms, but also by developing and applying different downstream techniques for easy recovery of fumaric acid from the fermented broth. This review presents the main methods for production and separation of fumaric acid, highlighting the advantages and disadvantages of these and the potential economic impact in industry.

Safety, Tolerability, and Pharmacokinetics of the Novel Antiviral Agent Ensitrelvir Fumaric Acid, a SARS-CoV-2 3CL Protease Inhibitor, in Healthy Adults

Ensitrelvir is a novel selective inhibitor of the 3C-like protease of SARS-CoV-2, which is essential for viral replication. This phase 1 study of ensitrelvir assessed its safety, tolerability, and pharmacokinetics of single (part 1, n = 50) and multiple (part 2, n = 33) ascending oral doses. Effect of food on the pharmacokinetics of ensitrelvir, differences in pharmacokinetics of ensitrelvir between Japanese and white participants, and effect of ensitrelvir on the pharmacokinetics of midazolam (a cytochrome P450 3A [CYP3A] substrate) were also assessed. In part 1, Japanese participants were randomized to placebo or ensitrelvir at doses of 20, 70, 250, 500, 1,000, or 2,000 mg. In part 2, Japanese and white participants were randomized to placebo or once-daily ensitrelvir at loading/maintenance dose 375/125 mg or 750/250 mg for 5 days. Most treatment-related adverse events observed were mild in severity and were resolved without treatment. Plasma exposures showed almost dose proportionality, and geometric mean half-life of ensitrelvir following the single dose was 42.2 to 48.1 h. Food intake reduced C_max and delayed T_max of ensitrelvir but did not impact the area under the curve (AUC), suggesting suitability for administration without food restriction. Compared with Japanese participants, plasma exposures were slightly lower for white participants. Ensitrelvir affected the pharmacokinetics of CYP3A substrates because of increase in AUC of midazolam coadministered with ensitrelvir 750/250 mg on day 6. In conclusion, ensitrelvir was well-tolerated and demonstrated favorable pharmacokinetics, including a long half-life, supporting once-daily oral dosing. These results validate further assessments of ensitrelvir in participants with SARS-CoV-2 infection.

Fumaric acid production by fermentation

The potential of fumaric acid as a raw material in the polymer industry and the increment of cost of petroleum-based fumaric acid raises interest in fermentation processes for production of this compound from renewable resources. Although the chemical process yields 112% w/w fumaric acid from maleic anhydride and the fermentation process yields only 85% w/w from glucose, the latter raw material is three times cheaper. Besides, the fermentation fixes CO2. Production of fumaric acid by Rhizopus species and the involved metabolic pathways are reviewed. Submerged fermentation systems coupled with product recovery techniques seem to have achieved economically attractive yields and productivities. Future prospects for improvement of fumaric acid production include metabolic engineering approaches to achieve low pH fermentations.

Bioproduction of fumaric acid: an insight into microbial strain improvement strategies

Fumaric acid (FA), a metabolic intermediate, has been identified as an important carbohydrate derived platform chemical. Currently, it is commercially sourced from petrochemicals by chemical conversion. The shift to biochemical synthesis has become essential for sustainable development and for the transition to a biobased economy from a petroleum-based economy. The main limitation is that the concentrations of FA achieved during bioproduction are lower than that from a chemical process. Moreover, the high cost associated with bioproduction necessitates a higher yield to improve the feasibility of the process. To this effect, genetic modification of microorganism can be considered as an important tool to improve FA yield. This review discusses various genetic modifications strategies that have been studied in order to improve FA production. These strategies include the development of recombinant strains of Rhizopus oryzae, Escherichia coli, Saccharomyces cerevisiae, and Torulopsis glabrata as well as their mutants. The transformed strains were able to accumulate fumaric acid at a higher concentration than the corresponding wild strains but the fumaric acid titers obtained were lower than that reported with native fumaric acid producing R. oryzae strains. Moreover, one plausible adoption of gene editing tools, such as Agrobacterium-mediated transformation (AMT), CRISPR CAS-9 and RNA interference (RNAi) mediated knockout and silencing, have been proposed in order to improve fumaric acid yield. Additionally, the introduction of the glyoxylate pathway in R. oryzae to improve fumaric acid yield as well as the biosynthesis of fumarate esters have been proposed to improve the economic feasibility of the bioprocess. The adoption of some of these genetic engineering strategies may be essential to enable the development of a feasible bioproduction process.

[Fumaric acid as therapeutic agent for multiple sclerosis]

After the approval of fumaric acid in February 2014 another first line agent is now available for the treatment of multiple sclerosis (MS). Along with the various beta interferon preparations, glatiramer acetate, teriflunomide and fumaric acid add to the repertoire of oral therapeutics for the initial treatment of relapsing remitting MS in daily practice. In order to employ these drugs in an individualized and precise medical manner and considering their efficacy and side effects, it seems worthwhile to learn the so far known mode of action and background history. Fumaric acid, as one of the newest drugs approved for MS, reveals the longest history as it was in use for decades as a treatment in psoriasis patients. Furthermore, fumaric acid is a good example for so far not extensively exploited option of drug reposition in medicine in general. The current review summarizes the outcomes of the clinical approval studies of fumaric acid in MS and discusses the dual mode of action, the immunomodulatory and tissue protective effect, as well as the reported adverse events under fumaric acid treatment. This review aims to serve an aid in the daily decision-making practice when choosing the baseline therapy for MS patients.